scholarly journals Genomic and phenomic insights from an atlas of genetic effects on DNA methylation

2020 ◽  
Author(s):  
Josine L Min ◽  
Gibran Hemani ◽  
Eilis Hannon ◽  
Koen F Dekkers ◽  
Juan Castillo-Fernandez ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genetic Variants ◽  
Complex Traits ◽  
Genetic Architecture ◽  
Genetic Variance ◽  
Genetic Factors ◽  
Additive Genetic Variance ◽  
Genetic Influences ◽  
Methylation Quantitative Trait Loci ◽  
Shared Genetic

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTL of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We reveal that the genetic architecture of DNAm levels is highly polygenic and DNAm exhibits signatures of negative and positive natural selection. Using shared genetic control between distal DNAm sites we construct networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic factors are associated with both blood DNAm levels and complex diseases but in most cases these associations do not reflect causal relationships from DNAm to trait or vice versa indicating a more complex genotype-phenotype map than has previously been hypothesised.

scholarly journals Genetic Variants of the NF-κB Pathway: Unraveling the Genetic Architecture of Psoriatic Disease

2021 ◽  
Vol 22 (23) ◽  
pp. 13004
Author(s):  
Rubén Queiro ◽  
Pablo Coto-Segura ◽  
Leire González-Lara ◽  
Eliecer Coto
Keyword(s):  
Genetic Variants ◽  
Genetic Architecture ◽  
Genetic Basis ◽  
Genetic Factors ◽  
Disease Susceptibility ◽  
Cell Types ◽  
Psoriatic Disease ◽  
Pharmacological Response ◽  
Light Chain Enhancer ◽  
Shared Genetic

Psoriasis is a multifactorial genetic disease for which the genetic factors explain about 70% of disease susceptibility. Up to 30–40% of psoriasis patients develop psoriatic arthritis (PsA). However, PsA can be considered as a “disease within a disease”, since in most cases psoriasis is already present when joint complaints begin. This has made studies that attempt to unravel the genetic basis for both components of psoriatic disease enormously difficult. Psoriatic disease is also accompanied by a high burden of comorbid conditions, mainly of the cardiometabolic type. It is currently unclear whether these comorbidities and psoriatic disease have a shared genetic basis or not. The nuclear factor of kappa light chain enhancer of activated B cells (NF-κB) is a transcription factor that regulates a plethora of genes in response to infection, inflammation, and a wide variety of stimuli on several cell types. This mini-review is focused on recent findings that highlight the importance of this pathway both in the susceptibility and in the determinism of some features of psoriatic disease. We also briefly review the importance of genetic variants of this pathway as biomarkers of pharmacological response. All the above may help to better understand the etiopathogenesis of this complex entity.

scholarly journals VTRNA2-1: Genetic Variation, Heritable Methylation and Disease Association

2021 ◽  
Vol 22 (5) ◽  
pp. 2535
Author(s):  
Pierre-Antoine Dugué ◽  
Chenglong Yu ◽  
Timothy McKay ◽  
Ee Ming Wong ◽  
Jihoon Eric Joo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Genetic Variation ◽  
Genetic Factors ◽  
Disease Association ◽  
Country Of Birth ◽  
Cpg Site ◽  
Multiple Case ◽  
Metastable Epiallele ◽  
Methylation Quantitative Trait Loci

VTRNA2-1 is a metastable epiallele with accumulating evidence that methylation at this region is heritable, modifiable and associated with disease including risk and progression of cancer. This study investigated the influence of genetic variation and other factors such as age and adult lifestyle on blood DNA methylation in this region. We first sequenced the VTRNA2-1 gene region in multiple-case breast cancer families in which VTRNA2-1 methylation was identified as heritable and associated with breast cancer risk. Methylation quantitative trait loci (mQTL) were investigated using a prospective cohort study (4500 participants with genotyping and methylation data). The cis-mQTL analysis (334 variants ± 50 kb of the most heritable CpG site) identified 43 variants associated with VTRNA2-1 methylation (p < 1.5 × 10−4); however, these explained little of the methylation variation (R2 < 0.5% for each of these variants). No genetic variants elsewhere in the genome were found to strongly influence VTRNA2-1 methylation. SNP-based heritability estimates were consistent with the mQTL findings (h2 = 0, 95%CI: −0.14 to 0.14). We found no evidence that age, sex, country of birth, smoking, body mass index, alcohol consumption or diet influenced blood DNA methylation at VTRNA2-1. Genetic factors and adult lifestyle play a minimal role in explaining methylation variability at the heritable VTRNA2-1 cluster.

scholarly journals Estimation of non-additive genetic variance in human complex traits from a large sample of unrelated individuals

2021 ◽  
Author(s):  
Valentin Hivert ◽  
Julia Sidorenko ◽  
Florian Rohart ◽  
Michael E. Goddard ◽  
Jian Yang ◽  
...  
Keyword(s):  
Complex Traits ◽  
Genetic Variance ◽  
Additive Genetic Variance ◽  
Large Sample ◽  
Human Complex

scholarly journals Heritability of DNA methylation in threespine stickleback (Gasterosteus aculeatus)

Genetics ◽  
2021 ◽  
Vol 217 (1) ◽  
Author(s):  
Juntao Hu ◽  
Sara J S Wuitchik ◽  
Tegan N Barry ◽  
Heather A Jamniczky ◽  
Sean M Rogers ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genetic Architecture ◽  
Gasterosteus Aculeatus ◽  
Additive Genetic Variance ◽  
Natural Populations ◽  
Threespine Stickleback ◽  
Phenotypic Change ◽  
Cpg Sites ◽  
Cis And Trans ◽  
Methylation Variation

Abstract Epigenetic mechanisms underlying phenotypic change are hypothesized to contribute to population persistence and adaptation in the face of environmental change. To date, few studies have explored the heritability of intergenerationally stable methylation levels in natural populations, and little is known about the relative contribution of cis- and trans-regulatory changes to methylation variation. Here, we explore the heritability of DNA methylation, and conduct methylation quantitative trait loci (meQTLs) analysis to investigate the genetic architecture underlying methylation variation between marine and freshwater ecotypes of threespine stickleback (Gasterosteus aculeatus). We quantitatively measured genome-wide DNA methylation in fin tissue using reduced representation bisulfite sequencing of F1 and F2 crosses, and their marine and freshwater source populations. We identified cytosines (CpG sites) that exhibited stable methylation levels across generations. We found that additive genetic variance explained an average of 24–35% of the methylation variance, with a number of CpG sites possibly autonomous from genetic control. We also detected both cis- and trans-meQTLs, with only trans-meQTLs overlapping with previously identified genomic regions of high differentiation between marine and freshwater ecotypes. Finally, we identified the genetic architecture underlying two key CpG sites that were differentially methylated between ecotypes. These findings demonstrate a potential role for DNA methylation in facilitating adaptation to divergent environments and improve our understanding of the heritable basis of population epigenomic variation.

scholarly journals Leveraging DNA methylation quantitative trait loci to characterize the relationship between methylomic variation, gene expression and complex traits

2018 ◽  
Author(s):  
Eilis Hannon ◽  
Tyler J Gorrie-Stone ◽  
Melissa C Smart ◽  
Joe Burrage ◽  
Amanda Hughes ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Genetic Variation ◽  
Quantitative Trait Loci ◽  
Quantitative Trait ◽  
Complex Traits ◽  
Common Genetic Variation ◽  
Online Data ◽  
The Relationship ◽  
Methylation Quantitative Trait Loci

ABSTRACTCharacterizing the complex relationship between genetic, epigenetic and transcriptomic variation has the potential to increase understanding about the mechanisms underpinning health and disease phenotypes. In this study, we describe the most comprehensive analysis of common genetic variation on DNA methylation (DNAm) to date, using the Illumina EPIC array to profile samples from the UK Household Longitudinal study. We identified 12,689,548 significant DNA methylation quantitative trait loci (mQTL) associations (P < 6.52x10-14) occurring between 2,907,234 genetic variants and 93,268 DNAm sites, including a large number not identified using previous DNAm-profiling methods. We demonstrate the utility of these data for interpreting the functional consequences of common genetic variation associated with > 60 human traits, using Summary data–based Mendelian Randomization (SMR) to identify 1,662 pleiotropic associations between 36 complex traits and 1,246 DNAm sites. We also use SMR to characterize the relationship between DNAm and gene expression, identifying 6,798 pleiotropic associations between 5,420 DNAm sites and the transcription of 1,702 genes. Our mQTL database and SMR results are available via a searchable online database (http://www.epigenomicslab.com/online-data-resources/) as a resource to the research community.

scholarly journals Shared genetic background between children and adults with attention deficit/hyperactivity disorder

2019 ◽  
Author(s):  
Paula Rovira ◽  
Ditte Demontis ◽  
Cristina Sánchez-Mora ◽  
Tetyana Zayats ◽  
Marieke Klein ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Genetic Variants ◽  
Genetic Background ◽  
Genetic Architecture ◽  
Neurodevelopmental Disorder ◽  
Genome Wide Association Studies ◽  
Hyperactivity Disorder ◽  
Common Genetic Variants ◽  
Shared Genetic

AbstractAttention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

scholarly journals Visualizing genetic similarity at the symptom level: The example of learning disabilities

2010 ◽  
Vol 33 (2-3) ◽  
pp. 155-157
Author(s):  
Oliver S. P. Davis ◽  
Robert Plomin
Keyword(s):  
Learning Disabilities ◽  
Cognitive Abilities ◽  
Genetic Similarity ◽  
Structural Equation ◽  
Genetic Architecture ◽  
Genetic Factors ◽  
Psychological Traits ◽  
Equation Modelling ◽  
Symptom Level ◽  
Shared Genetic

AbstractPsychological traits and disorders are often interrelated through shared genetic influences. A combination of maximum-likelihood structural equation modelling and multidimensional scaling enables us to open a window onto the genetic architecture at the symptom level, rather than at the level of latent genetic factors. We illustrate this approach using a study of cognitive abilities involving over 5,000 pairs of twins.

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